The National Ovarian Cancer Prevention and Early Detection Study [CAS 7210] among women at increased genetic risk of ovarian cancer (aka GOG-199) is the cornerstone of CGB's intervention studies research portfolio. It is a non-randomized natural history study of risk-reducing salpingo-oophorectomy (RRSO) versus a novel ovarian cancer screening strategy (the ROCA algorithm). This study closed to new patient enrollment in November 2006, having accrued 2605 high-risk women (1029 surgery arm; 1576 screening arm). Prospective follow-up ended in November 2011, and the final analytic data base is now complete. Accomplishments to date include: (1) successfully completing subject accrual; (2) completing the research-based BRCA1/2 mutation testing for the 1,500 mutation-unknown study participants; (3) completing the central pathology review of 1037 risk-reducing salpingo-oophorectomy (RRSO) samples; (4) publishing a report detailing the rationale and design of the study, along with baseline characteristics of the women in each cohort; (5) developing a preliminary model of the factors which influence the choice of RRSO versus screening; (6) contributing 1,576 screening subjects to a published pooled analysis (with the Cancer Genetics Network: total = 4,000 subjects) of determinants of baseline CA-125 levels and of the performance characteristics of the ROCA algorithm, which demonstrated that pre-menopausal women should have an upper limit of normal cut-off=52, rather than 35 as customarily used; (7) creating a unique biospecimen repository for future translational research; and (8) negotiating a collaboration between GOG and CIMBA under which DNA and clinical data from our 1100 mutation carriers are being contributed to multiple pooled candidate gene association studies of BRCA-related breast and ovarian cancer risk, and two genome-wide association studies (GWAS), one for each BRCA gene. 32 published manuscripts have resulted from this collaboration, and an additional 7 are currently under review. Our Commentary proposing that bilateral salpingectomy might be a valuable ovarian cancer risk-reduction option has led to the development of a new GOG pilot study to test the feasibility of this approach in BRCA1/2 mutation carriers, and the Canadian province of British Columbia has implemented bilateral salpingectomy as a routine procedure in women undergoing benign hysterectomy and tubal ligation in its general population. A CIMBA manuscript describing what will be the definitive genotype/phenotype analysis of breast and ovarian cancer risk in 30,000 BRCA mutation carriers has been accepted for publication in JAMA, and data from another dozen candidate SNPs are in various stages of analysis and manuscript preparation. Our report describing that invasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 GOG-09199 RRSOs (BRCA1 carriers=4.6%, BRCA2 carriers=3.5%, and non-carriers=0.5% (p=0.0006) will appear shortly in the Journal of Clinical Oncology. In multivariable models, positive BRCA1/2 mutation status (p=0.0056), postmenopausal status (p=0.0023) and abnormal CA-125 levels and/or transvaginal ultrasound examinations (p0.0001) were associated with detection of clinically-occult neoplasms at RRSO. These data provide the best current estimates of the prevalence of clinically-occult serous pelvic malignancy at the time of RRSO. Additional analyses are now underway related to (1) the performance characteristics of the ROCA ovarian cancer screening algorithm in the pooled GOG-199/CGN data set (manuscript ready for submission); (2) testing/validation of the medical decision-making model related to choice between surgery and screening; (3) a description of baseline quality of life by study arm; (4) blinded pathology review of RRSO surgical pathology material to determine intra- and inter-observation concordance related to the diagnosis of proliferative lesions in the fallopian tube mucosa; (5) analysis of the prospective risk of breast and ovarian cancer based on the prospective follow-up of this cohort; (6) the relationship between ovarian size and circulating ovarian hormone levels; and (7) a pilot study evaluating a novel method for collecting ovarian cancer surface epithelial cells as translational research reagents. Methylation and mRNA profiling are currently being performed in collaboration with colleagues at Johns Hopkins. Multiple biospecimen-based translational research projects are both underway and planned. The Breast Imaging Pilot Study in Women from BRCA Mutation-Positive Families reached its accrual goal of 200 women from BRCA1/2 mutation-positive families; prospective follow-up ended in February 2010. A published analysis of baseline mammographic density (MD) has revealed no differences between mutation carriers and low-risk women. Analyses of MRI volume in carriers versus non-carriers and correlations between with MD are nearing completion. Our digitized mammographic images were used in a just-published collaboration with investigators from the University of Chicago to identify various novel imaging characteristics that are strongly correlated with BRCA mutation status; these computer-derived features may improve radiographic breast cancer risk stratification relative to standard mammography. Our breast duct lavage (BDL) study in the largest cohort of BRCA mutation carriers yet reported led us to abandon BDL as a research/risk stratification tool. DNA samples from mutation-positive BI participants have been contributed to our collaboration with CIMBA. We have published pilot data documenting that femtogram quantities of estrogen metabolites are detectable in both NAF and BDL fluid, and demonstrated that circulating estrogens and estrogen metabolites are strongly and positively correlated when measured in both tissues. This suggests that future etiologic studies could utilize the more readily obtainable serum hormone levels as a reliable surrogate measure of exposure at the tissue level. Our most recent psychosocial study using the Breast Imaging Study patients revealed that false positive cancer screening test results were not associated with large increases in cancer risk perception, cancer worry or increased uptake of risk-reducing surgery. However, cancer-specific worry was an independent predictor of uptake of risk-reducing surgery; this domain warrants consideration when counseling high-risk women regarding risk-reducing interventions.